The silent threat of submicroscopic Plasmodium infections during pregnancy
Authors: Silvia Maria Fátima Di Santi
Journal: The Lancet Global Health (2023)

The burden of malaria during pregnancy has a major effect on the life expectancy of children because low birth weight is a risk factor for neonatal mortality. On the African continent, 13·3 million pregnant women were exposed to malaria in 2021. New recommendations from WHO indicate intermittent preventive treatment with sulfadoxine-pyrimethamine for Plasmodium falciparum infections, regardless of the number of pregnancies.1WHOWorld malaria report 2022. World Health Organization, Geneva2022Google Scholar In a systematic review and meta-analysis published in The Lancet Global Health, Anna Maria van Eijk and colleagues2Mahamar A Andemel N Swihart B et al.Malaria infection is common and associated with perinatal mortality and preterm delivery despite widespread use of chemoprevention in mali: an observational study 2010 to 2014.Clin Infect Dis. 2021; 73: 1355-1361Crossref PubMed Scopus (9) Google Scholar described the results of studies published from Jan 1, 1997, to Nov 10, 2021, using aggregated data (23 studies) and individual participant data (45 studies). The results revealed that the median prevalence estimates were 13·5% for submicroscopic infections and 8·0% for microscopic Plasmodium infections. Submicroscopic infections detected by nucleic acid amplification test were positive in 58·7% of the pregnant women. The highest rates were detected in the Americas (73·3%), Asia (67·2%), and Africa (56·5%). It is known that pregnant women living in malaria transmission areas can develop partial immunity, remaining asymptomatic with low parasitaemia in the peripheral blood. This low parasitaemia is not detected by routine malaria tests (eg, thick blood smears or rapid diagnostic tests). However, higher parasitaemias can occur in the placentas of pregnant women infected with P falciparum due to the sequestration of parasites. Erythrocytes infected by P falciparum express the VAR2CSA protein on the surface, which binds to chondroitin sulfate A present in placental cells. Even in asymptomatic infections, placental malaria can lead to serious events, such as maternal anaemia, low birthweight deliveries, and increased maternal and infant mortality.3Weckman AM Conroy AL Madanitsa M et al.Neurocognitive outcomes in Malawian children exposed to malaria during pregnancy: An observational birth cohort study.PLoS Med. 2021; 18e1003701Crossref PubMed Scopus (4) Google Scholar Neurodevelopment can also be affected by placental malaria, as has been shown in Malawian children who had delayed language development.4Garrison A Boivin MJ Fiévet N et al.The effects of malaria in pregnancy on neurocognitive development in children at 1 and 6 years of age in Benin: a prospective mother-child cohort.Clin Infect Dis. 2022; 74: 766-775Crossref PubMed Scopus (4) Google Scholar In Benin, impaired motor skills and difficulties in cognitive processing abilities have been reported in children.5Dombrowski JG Barateiro A Peixoto EPM et al.Adverse pregnancy outcomes are associated with Plasmodium vivax malaria in a prospective cohort of women from the Brazilian Amazon.PLoS Negl Trop Dis. 2021; 15e0009390Crossref PubMed Scopus (12) Google Scholar Regarding Plasmodium vivax, this species accounts for only 0·3% of malaria cases in Africa. However, in other malaria-endemic regions, P vivax is of great epidemiological importance, contributing 39·7% of cases in southeast Asia, 18·0% in the eastern Mediterranean region, 31·9% in the western Pacific region, and 71·5% in the Americas.1WHOWorld malaria report 2022. World Health Organization, Geneva2022Google Scholar Although P vivax-infected erythrocytes do not present the phenomenon of sequestration in the placenta, this species can also lead to anaemia in the mother and low birthweight in the child. In a study conducted in the Brazilian Amazon, P vivax malaria in pregnant women was associated with placental tissue damage and poor gestational outcomes, particularly in the first trimester of pregnancy.6Van Eijk AM Stepniewska K Hill J et al.Prevalence of and risk factors for microscopic and submicroscopic malaria infections in pregnancy: a systematic review and meta-analysis.Lancet Glob Health. 2023; (published online June 2.)https://doi.org/10.1016/S2214-109X(23)00194-8Summary Full Text Full Text PDF Google Scholar Van Eijk and colleagues reported that in Africa, the percentage of submicroscopic infections decreased with increasing malaria transmission.2Mahamar A Andemel N Swihart B et al.Malaria infection is common and associated with perinatal mortality and preterm delivery despite widespread use of chemoprevention in mali: an observational study 2010 to 2014.Clin Infect Dis. 2021; 73: 1355-1361Crossref PubMed Scopus (9) Google Scholar This finding is in line with the pattern proposed by Bousema and colleagues7Bousema T Okell L Felger I Drakeley C Asymptomatic malaria infections: detectability, transmissibility and public health relevance.Nat Rev Microbiol. 2014; 12: 833-840Crossref PubMed Scopus (412) Google Scholar that, at a global scale, the proportion of submicroscopic Plasmodium infections is lower in areas of high transmission (prevalence of thick blood smear ≥5%) than in areas of low transmission (prevalence of thick blood smear ≤10%), where the percentage of submicroscopic infections can reach 70–80%. Van Eijk and colleagues2Mahamar A Andemel N Swihart B et al.Malaria infection is common and associated with perinatal mortality and preterm delivery despite widespread use of chemoprevention in mali: an observational study 2010 to 2014.Clin Infect Dis. 2021; 73: 1355-1361Crossref PubMed Scopus (9) Google Scholar also noted that nucleic acid amplification tests revealed that in Asia, P vivax infections were more likely to be submicroscopic than P falciparum infections. On the other hand, in Africa, the proportion of microscopic and submicroscopic P falciparum infections during pregnancy were similar. In Asia and the Americas, P falciparum was responsible for 75% of microscopic infections and 52% of submicroscopic infections. Asymptomatic infections in pregnant women have been reported in an area of low transmission outside the Amazon basin in Brazil. Hristov and colleagues8Hristov AD Sanchez MC Ferreira JJ et al.Malaria in pregnant women living in areas of low transmission on the southeast Brazilian coast: molecular diagnosis and humoural immunity profile.Mem Inst Oswaldo Cruz. 2014; 109: 1014-1020Crossref PubMed Scopus (16) Google Scholar reported positivity of 1·6% in pregnant women tested by thick blood smear, whereas positivity in PCR assays (quantitative PCR and nested PCR) was 5·6%. P vivax was detected in three (2%) of 125 pregnant women and Plasmodium malariae in four (3%) of 125 pregnant women. Zoonotic transmission is suggested in this region, located in the Atlantic Forest biome on the Brazilian coast.8Hristov AD Sanchez MC Ferreira JJ et al.Malaria in pregnant women living in areas of low transmission on the southeast Brazilian coast: molecular diagnosis and humoural immunity profile.Mem Inst Oswaldo Cruz. 2014; 109: 1014-1020Crossref PubMed Scopus (16) Google Scholar Although zoonotic malaria caused by Plasmodium knowlesi was not addressed by van Eijk and colleagues, this species also poses a challenge to efforts to eliminate transmission and it is important to know its impact in pregnancy. In southeast Asia, Malaysia faces increasing cases of zoonotic malaria due to P knowlesi.1WHOWorld malaria report 2022. World Health Organization, Geneva2022Google Scholar However, little is known about the effects of P knowlesi malaria during pregnancy, and further studies are needed to establish the burden of P knowlesi in pregnant women, including the prevalence of submicroscopic parasitaemia. Submicroscopic parasitaemias associated with asymptomatic Plasmodium infection are a challenge for malaria elimination campaigns because these silent reservoirs are invisible to malaria control programmes. Even harbouring low parasitaemias, these individuals can infect mosquitoes and disseminate parasites.9Lindblade KA Steinhardt L Samuels A Kachur SP Slutsker L The silent threat: asymptomatic parasitemia and malaria transmission.Expert Rev Anti Infect Ther. 2013; 11: 623-639Crossref PubMed Scopus (317) Google Scholar Van Eijk and colleagues showed that more than half of Plasmodium infections during pregnancy were submicroscopic. Despite not representing a risk for individuals in general, asymptomatic infections during pregnancy can lead to maternal anaemia, premature births, and low birthweight.10Cottrell G Moussiliou A Luty AJ et al.Submicroscopic Plasmodium falciparum infections are associated with maternal anemia, premature births, and low birth weight.Clin Infect Dis. 2015; 60: 1481-1488Crossref PubMed Scopus (103) Google Scholar Van Eijk and colleagues highlight the high prevalence of submicroscopic parasitaemias during pregnancy, which are a threat to the health of mothers and babies. The data presented show the need for more sensitive specific diagnostic tests to be applied in prenatal care, avoiding poor gestational outcomes, and saving lives. I declare no competing interests. Prevalence of and risk factors for microscopic and submicroscopic malaria infections in pregnancy: a systematic review and meta-analysisDuring pregnancy, submicroscopic infections are more common than microscopic infections and are associated with fever in Africa. Malaria control in pregnancy should target both microscopic and submicroscopic infections. Full-Text PDF Open Access